Analysis Of Genetic Damage Characteristics Of Nervous System And Other Organs And Tissues In APP/PS1 Mice

Alzheimer’s disease（AD）is a serious progressive neurodegenerative disease.Previous studies have found that genetic damage in peripheral blood lymphocytes of patients with AD is significantly higher than that of controls.In view of the fact that the rate of genetic damage generally increases with age,high genetic damage is often one of the foundations of degenerative diseases.In order to explore the association between genetic damage of nervous system and other tissues and AD,APP^swe/PS1^{d E9}double transgenic mice associated with AD were used as AD model in this study.To explore the changes of telomere length and micronucleus rate of bone marrow polychromophilic erythrocytes with age in the nervous system and other organs and tissues and their relationship with the molecular pathological phenotype of AD,so as to provide a new scientific basis for understanding the pathogenesis of AD.APP^swe/PS1^{d E9} mice at the age of 6,8,10,12,and 14 months and wild-type（WT）control mice with 4 males and 4 females were randomly selected.The behavioral classic Morris water maze test was used to evaluate the cognitive ability of the mice.The results showed that the cognitive ability of all mice decreased with the increase of month age（P<0.05）.However,at the same age,the cognitive ability of AD mice was significantly lower than that of WT mice of the same age（P<0.05）.There was no significant difference in cognitive ability between different sexes.In order to reveal the molecular phenotype of APP^swe/PS1^{d E9} mice,the contents of amyloid plaque markers Aβ₄₀ and Aβ₄₂ and the Aβ₄₂/Aβ₄₀ ratio of hippocampus cells in cognitive functional area of AD mice were detected by ELISA.In conclusion,the contents of Aβ₄₀ and Aβ₄₂ and the ratio of Aβ₄₂/Aβ₄₀ in hippocampus of AD mice were positively correlated with age.Compared with AD mice at 6 months of age,the contents of Aβ₄₀ and Aβ₄₂ in hippocampus were significantly increased from 12 months of age（P=0.000）,and the production rate of Aβ₄₂/Aβ₄₀ was significantly increased（P=0.000）.The peak values of Aβ₄₀,Aβ₄₂ and Aβ₄₂/Aβ₄₀ in hippocampus of AD mice of different genders were slightly higher in female AD mice than in male AD mice,but there was no significant difference.In conclusion,the AD mice used had the corresponding AD behavior and molecular phenotype.We further evaluated the level of genetic damage in the nervous system of AD mice,and measured telomere length（TL）in different brain tissue cells involved in cognitive function by real-time quantitative PCR（RT-q PCR）.The results showed that the cell TL of all AD mice was significantly lower than that of the control group at the same age.The TL of prefrontal cells related to behavioral decision and judgment was significantly shorter than that of the control group（P=0.014）.The TL of pituitary cells associated with hormone release and memory assistance was significantly shortened（P=0.014）.The TL related to short-term memory and cognition was significantly shortened（P<0.02）.The small brain cell TL associated with balance and auxiliary cognition was significantly shortened（P=0.015）.The study proved that with the increase of age,the rate of TL shortening in AD mice was significantly faster than that in the control group,suggesting that the rate of nerve cell senescence was higher than that in the control group.In order to search for potential biomarkers related to AD in other organs and tissues other than the nervous system of AD individuals,the study analyzed the TL of skin and colon cells,which accounted for the largest proportion of the tested animals,and found that the TL of skin and colon cells in AD mice were significantly shorter than that in WT mice（P=0.000）.It is necessary to compare the TL changes of these organs and nervous system cells in the later work.In order to evaluate the overall genetic damage level of AD mice,bone marrow polychromatic erythrocyte micronucleus（MNPCE）test was used to compare the MNPCE frequency of WT and AD mice in different age groups.The results showed that MNPCE frequency of all tested animals was proportional to age.The MNPCE frequency of AD and WT mice at 14 months increased by 10.7%and 4.6%,respectively,compared with that of WT mice at 6 months.The MNPCE frequency of AD mice at 14months was about twice that of WT mice,the difference was extremely significant（P<0.01）.The results showed that the genomic stability of AD mice was significantly lower than that of the same age control.In conclusion,this study confirmed that APP^swe/PS1^{d E9} transgenic AD mice are similar in behavior and molecular phenotype to humans,which is a good AD animal model.The TL contrast of the cells of nervous system,skin and digestive organ was significantly shortened,suggesting that the aging rate of AD animal cells was increased.High genetic damage in TL and MNPCE in AD mice may be an auxiliary biological marker for early diagnosis of AD.